Synthetic terpenoid compounds for insect control

ABSTRACT

Ethers of open chain terpenoid compounds and their monoepoxides were synthesized and found to mimic the juvenile hormones of insects and to be extremely effective as insect control agents.

United States Patent [191 Bowers Sept. 9, 1975 SYNTHETIC TERPENOIDCOMPOUNDS FOR INSECT CONTROL [56] References Cited [75] Inventor:William S. Bowers, Geneva, NY. UNITED STATES PATENTS 73 Assignee; TheUnited states f America as 3,453,362 7/1969 Cruickshank 424/84represented by the Secretary of 3,790,680 2/1974 Lee 424/278Agriculture, Washington, DC.

Primary ExaminerV. D. Turner [22] Filed: Apr. 23, 1974 App]. No.:463,331

Related U.S. Application Data Continuation of Ser. No. 78,577, Oct. 6,1970, abandoned.

Attorney, Agent, or FirmM. Howard Silverstein; Max D. Hensley; WilliamE. Scott [5 7 1 ABSTRACT Ethers of open chain terpenoid compounds andtheir monoepoxides were synthesized and found to mimic the juvenilehormones of insects and to be extremely effective as insect controlagents.

18 Claims, No Drawings SYNTHETIC TERPENOID COMPOUNDS FOR INSECT CONTROLA non-exclusive, irrevocable, royaltyfree license in l the inventionherein described throughout the world for all purposes of the UnitedStates Government, with the power to grant sublicenses for suchpurposes, is hereby granted to the Government of the United States ofAmerica.

This application is a continuation of application Ser. No. 78,577, filedOct.-6, 1970, now abandoned.

This invention relates to insect control and more particularly tocompounds and 'to the preparation of compounds that have high juvenilehormone activity and which are highly ovicidal to insect eggs.

There is considerable concern throughout the world used to controlstored product insects and many social pests such as fireants andtermites. ln addition, it may be feasible to use these compounds infield applications to control a wide variety of insects, the toxicity ofthe compounds to vertebrates should be insignificant, and the cost toproduce them commercially should be very competitive with that of wellknown insecticides.

One object of this invention is to provide a means for achievingselective, safe, economical control of insect pests.

Another object is to provide chemical compounds that prevent insectmaturation when applied topically, when fed to insects or when appliedin a vapor state as a fumigant, to an insect in an immature stage ofgrowth.

A further object of this invention is to provide compounds thatadversely affect the biological function of insects, particularly theirability to mature to an adult stage. I

In general, according to the present invention the terpenoid ethers andtheir corresponding epoxides are synthesized and found to prevent insectmaturation when applied to immature stagesof several species of insectsby topical application, by feeding or by fumiga; tion (exposure tovapor). Thus an immature insectexposed to these compounds is unable tometamorphose, into a normal adult. Topical application of as little as10.0 nanogram s (0.0] ,ug) of the more active cornpounds in this seriesis sufficient to prevent metamorphosis. The insect which emerges fromthe treated pupa retains immature genitalia which preclude copulationand reproduction. The insects die shortly after molting to this adultoidcondition. Also, when used as a vapor or as a dip treatment for eggs thecompounds drastically reduce egg hatch.

The compounds of this invention having the following general formula.

wherein Y is 5 z; EH:

R-C=CH or R- CH 1O R-is a straight chain alkyl containing froml-2'carbon atoms such as CH CH CH .r is a number from -1 to'2, and Z isone of the following groups: I

. H2cH2 0 2 n in which n is 0-3;

CH; CH3

in which n is ()3.

The terpenoid portions of the compounds were prepared in part by theMarc Juliasynthesis [Bull. Soc.

35 Chem. France 1072, (1960)] as outlined below.

0 CH2 H, CH

Oxidation was performed with chromic acid solution in acetone [J. Chem.Soc. 2548( 1953)] 65 The vinyl alcohols are prepared by the grignardreaction with vinyl magnesium bromide (or chloride) in tetrahydrofuran.

The vinyl alcohols were converted to the allylic bromides by treatmentwith hydrogen bromide in aqueous or acetic acid solution. Thus, analiquot of the vinyl alcohol was added dropwise to a rapidly stirred icecold aqueous or acetic acid solution containing 2 molar equivalents ofhydrogen bromide. When addition was complete, stirring was continued for20 minutes and then the reaction mixture was poured into an excess ofice cold 5% sodium carbonate solution, extracted with diethyl ether andwashed to neutrality with water. After drying the ethereal extracts oversodium sulfate and removal of the solvent in vacuo, the allylic bromideswere obtained in nearly quantitative yield.

3 R CH R Another series of compounds in which the terpenoid carbon chainwas one carbon longer were prepared in a similar manner except that thebromides were prepared by a continuation of the Julia synthesis asfollows:

HBr

in which n is O to 3;

were synthesized by coupling the foregoing bromides with the respectivealcohols of A to form the corresponding ethers by refluxing the bromidesor stirring at room temperature for several hours with a slight molarexcess of the alcohols and a base such as powdered potassium hydroxideor potassium teritary butoxide in an anhydrous solvent such as diethylether, dimethoxyethane or dimethyl formamide. Alternatively, thereactants were sealed in a small reaction bomb and place in an oven at150C for 2-4 hours.

The reaction mixture was then diluted with water and extracted severaltimes with hexane. The hexane extracts were combined and washed toneutrality with water. The hexane portion was dried over sodium sulfateand the solvent removed in vacuo to yield the crude ethers.

Compounds of the general formula wherein Y is -C CH or RCCH R is astraight chain alkyl containing from one to two carbon atoms such as CHCH CH x is a number from 1 to 2; and A is CH CH -O(CH CH,

base

wherein Y is R is a straight chain alkyl containg from 1-2 carbon wereprepared by stirring the terpenoid alcohols for 2 atoms such as CH CH CHx is a number from hours at room temperature with the appropriate vinyll to 2; and E is ether in the presence of a catalytic amount ofhydrochloric acid.

/o CH2COO(CH2),,CH or CH- CHH2 CH" R CH2 Hcl in which n is 0 to l R*=c|-l cH t :=cHcH oH HO(CH ),,CH;, were prepared from the terpenoidalcohols.

. CH, R Cl-l The allyhc terpenoid alcohols were prepared from o theircorresponding vinyl analogs by chromic acid oxi R C=CH(CH2)2C=CH(CH2)J 2Il dation [1. Chem. Soc. 2548 (1953)] to the conjugated H aldehyde,followed by reduction to the primary alcohol with a metal hydride Suchas SQdiUm borohydride in The reaction was complete in 1 hour and thereaction methanol lithium aluminum hydride in ether' mixture wasextracted with diethyl ether and washed successively with 5% aqueoussodium carbonate and water. The ethereal extract was dried overanhydrous sodium sulfate. The crude product was isolated by 2)2 2- 2)2evaporation of the solvent in vacuo.

OH The desired compounds were purified by column chromatography overfiorisil as previously described.

, H R Purity was determined by gas-lipid chromatography NaBH, l andinfra-red spectroscopy to be greater than 99%.

=CH(CHZ)2C=CHCHO R C?CH(CHZ)Z =CHCH2OH All of the ethers prepared by theforegoing syntheses were then epoxidized by stirring them in an organicsol- The P y halides of E, (Br l'b -zln CH3, or vent such as benzene,chloroform or methylene chlo- 1. R CH R Br ride during the addition of aslight molar excess of an O epoxidizing agent such as m-chloroperbenzoic acid. Epoxidation occurred selectively at the terminal dou-CH CH H ble bond within a few minutes to lhour. The reaction mixture waswashed with 5% sodium carbonate and were coupled with the terpenoidalcoholsunder basic then with water to neutrality, and dried over sodiumconditions in a reaction bomb, under reflux, or by stirsulfate. Solventwas removed in vacuo. ring at room temperature for an extended period ofThe epoxides were purified by chromatography over time. florisil aspreviously described.

CH, R R RJ=CH(CH2)- ,C=CHCH2OH EBTR- =CH(CH2)2C=(HCH2OE use The crudeethers were purified by chromatography Purity was ascertained bygas-liquid chromatography overflorisil as previously described. Puritywas deterand infrared spectroscopy to be greater than 99%. mined bygas-liquid chromatography and infra-red The compounds and their epoxidesprepared by the spectroscopy to be greater than 99%. above proceduresare shown in Table 1.

Compounds of the general structure Although the general procedures justdescribed are undoubtedly adequate for those skilled in the art, thefollowing examples further illustrate the preparation of compoundswithin the scope of each of the general Ha structures shown above.

R i (CH=M- -'=C (C 2), Synthesis of Compound 49 in Table l wherein In a500 ml. boiling flask, 10.8 g. ethylene glycol Y is butyl ether, wascombined with 10.2 g. potassium tertbutoxide and I0 g. geranyl bromidein 100 ml. dimethoxyethane. The reaction mixture was stirred at room(H.l H. temperature for 16 hrs. and then poured into 200 ml. J CH of ofhexane and washed 2X with water and 1X with saturated aqueous sodiumchloride solution. The organic layer was dried over anhydrous sodiumsulfate and the W hexane removed in vacuo. 13.6 g. of crude compound RStra'ght cham alkyl comammg from F2 carbon was recovered and found to besuitable for the subseatoms such as CH;,, CH=,CH

I quent epoxidatlon. x is a number from 1 to 2; and n is a number from 0to 3 Epoxidation of Compound 49 in Table l Dissolved 4 g. of theCompound 49 in 50 ml. CH Cl and with stirring added 3.2 g.m-chloroperbenzoic acid in aliquots. Stirred 30 min. and then made thesolution basic with 10% aqueous sodium carbonate. Stripped 011' thesolvent in vacuo. Residue was dissolved in diethyl ether and washed in aseparatory funnel with 10% sodium carbonate 2X, and water 2X. Driedorganic layer over anhydrous sodium sulfate. Stripped off solvent invacuo. Crude epoxide yield was 3.8 gm. Fractionation of the crudeepoxide'over 60 gm. of florisil by stepwise elution with increasingconcentrations of diethyl, ether in hexane gave 3.0 g. pure epoxide.(Compound No. 57)

Synthesis of Compound 65 in Table 11 CH vCH:

Combined 10 gm. glycerol acetonide and 5.4 gm. po-

tassium tertbutoxide in 50 ml. dimethoxyethane and v Epoxidation ofCompound 65 in Table-11 locuiui m 8 Dissolved 1.3 g. of Compound in 30ml. CH Cl and added in aliquots 1.0'gml of m-Chloroperbenzoic acid.Reaction stirred 30 min. Solution made basic with 10% aqueous sodiumcarbonate. Stripped off solvent in vacuo. Residue dissolved in diethylether and washed in a separatoryfunnel with 10% sodium carbonate 2X andwith water 2X.- Dried over anhydrous'sodium sulfate. Crude epoxide,Compound 73, was 1.3 g.

The crude'epoxide was fractionated by column chromatography as specifiedfor Compound 65. Yield of pure epoxide, Compound 73, was 950 mg.(Compound Synthesis. hc fiipou qsl if; Table 1 Epoxidation of Compound89 in Table l I H. OCH COO Dissolved 1 gm. of Compound 81 in 25 ml. ofCHCl l-lexane (3-2) containing 0.4 gm sodium bicarbonate with stirringin an ice bath. To this was added dropwise 1.0 gm. m-chloroperbenzoicacid in 25 ml. of CHCl Hexane (3-2). After addition, stirring in the icebath was maintained for 15 min. Sodium sulfite was added to destroy anyexcess peracid. The reaction mixture was dissolved in about 200 ml; ofdiethyl ether and washed in a separatory funnel with 10% aqueous sodiumcarbonate 2X and water 2X. Organic layer was dried over anhydrous sodiumsulfate and the solvent stripped off in vacuo. Yield of crude Compound89 was 1.26 gm.

The crude Compound 89 was fractionated over 30 gm. of florisil asspecified for Compound 81 and 770 mg. of pure Compound 89 was obtained.Analysis by gas-chromatography and infrared. (Compound 89) Synthesis ofCompound .1 13 in Table l Dissolved g. geraniol in 50 ml.dimethoxyethane containing 3.5 g. potassium tert-butoxide with stirringfor 30 min. Added 4.4 g. epibromohydrin and stirred at room temperaturefor 3 hrs. Filtered, dissolved in about 250 ml. diethyl ether and washedwith water 3X in a separatory funnel. The organic layer was dried overanhydrous sodium sulfate and the solvent stripped off in vacuo. Yield ofcrude ether was 7.6 gm. The crude ether was fractionated by columnchromatography over 150 gm. of florisil. Stepwise elution with increasing concentrations of ether in hexane gave 2.24 gm. of pure Compound 1l3.

Epoxidation of Compound 113 in Table I Mil. 2

. i v g O M.OCH2JH\CH2 1 Dissolved 2.24 g. of Compound 1 13 in 50 ml. CHCl and with stirring added 2.2g. m-chloroperbenzoic acid in aliquots.Stirred an additional 30 min., made basic with aqueous sodium carbonate,dissolved in 200 ml. diethyl ether and washed with 10% aqueous sodiumcarbonate 2X and with water 2X in a separatory funnel. Organic layerdried over anhydrous sodium sulfate. Yield of crude Compound 121 was 2.0gm. Column chromatography of Compound 121 over 60 gm. florisil bystepwise elution with increasing concentrations of diethyl ether inhexane gave 713 mg. of pure Compound 121. Analysis by gas-chromatographyand infrared. (Compound 121) Synthesis of Compound 145 in Table I OH CH.,=CHOC2H,-,

Geraniol (10 gm.) in ml. diethyl ether was added dropwise to 14 g. ethylvinyl ether containing 1 drop of concentrated HC]. After addition,stirring was maintained for 2 hrs. in a warm water bath (ca. C.).

The reaction mixture was dissolved in 200 ml. of diethyl ether andwashed in a separatory funnel with 5% aqueous sodium carbonate IX, andwater 3X. The organic layer was dried over anhydrous sodium sulfate. Thesolvent was stripped off in vacuo. The crude acetal yield was 14.5 gm.

Filtration of 5 gm. of the acetal in hexane through a column containing150 gm. of florisil gave a quantitative return of 5 gm. of pure acetalCompound 145. Purity ascertained by gas-chromatography and infraredanalysis. I

Epoxidation of Compound 145 in Table 1 To a stirred solution of 5 gm. ofCompound 145 in ml. hexane was added dropwise 4.94 gm. mchloroperbenzoicacid dissolved in 100 ml. CH Cl After addition, stirring was continuedfor 20 min. Excess peracid'was destroyed with sodium sulfite. Thereaction'mixture was made basic with 5% aqueous potassium hydroxide andthe solvent stripped off in vacuo. The residue was dissolved indiethylether and washed in a separatory funnel .with 5% aqueouspotassium hydroxide IX and with water 3X.

Organic layer was dried over anhydrous sodium sulfate and the solventstripped off in vacuo. Yield of crude Compound 153 was 5.0 gm.

Fractionization of 5.0 gm. of Compound 153 by column chromatography over100 gm. of florisil by stepwise elution with increasing concentrationsof diethyl ether in hexane gave 3.0 gm. of pure Compound 153.

Analysis by gas-chromatography and infrared. (Com-.

10 nanograms (0.01 #g) of several compounds (i.e. 25,

26, 28, 57, 73) resulted in the retention of complete pupal genitaliaafter the ultimate molt toward the adult beetle. Topical application ofv 100 nanograms (0.1 pg) resulted in the development of pupal-adultintermediates.

Topical application of somewhat greater amounts of compounds 76, 89,121, 153, were required to induce retention of pupal genitalia and/orproduce pupal-adult intermediates in Tenebrio. In all cases the affectedinsects were unable to form normal adults and died during or shortlyafter their ultimate molt without significant feeding and without anyreproduction.

Table III shows the effects of compounds 25, 26, 28, 57, 73, 81, 89,153, on the Mexican bean beetle. Topical application of nanogram tomicrogram quantities of these compounds prevents normal adultdevelopment and the insects die during the ultimate molt. Topicaltreatment of Mexican bean beetle eggs with extremely dilute acetonesolutions of these compounds caused severe reduction in egg hatch.

Table IV shows the morphogenetic effects of compounds 25, 26, 28, 57,73, 89, 121, 153, on Tenebrio after exposure of the pupae to the vaporsof these compounds. These results exemplify the potential use of thecompounds as fumigants.

TABLE 1 7 12 TABLE 1 Cntinu ed Synthcsi/cd Iurpcnuid Fthcrs and Their[ipoxidus Synthesized 'l'crpcnoid Elhurs and Thuir Epoxidcs l5 7 16TABLE l continued TABLE l C0ntinued :uh-wwd lclpuuml Llhcrs and lhuiriipnxidgs Synthesized Turpcnuid ,Elhurs and Their Epuxidus it CH3 5 CH3(VH3 v C I C v (f (I) (I) (:6 MOCH CH-CH I0 77 o ()CH:CH-CH:

(H CH I CH CH C v I v W v I W (I) 0 7 OCH. .CHCH v v 78 o v v ()CH CH H-L 1 CH CH C I I H" H:x

TABLE 1 Continued TABLE 1 Continued S \mhcsizcd 'I'urpcnuid Elhcrs and'I'hcir Epuxidcs o o cH ocH cH Ill '1 ABLE 1 Continued Synthesized 'lcrpenoitl lithers and Their Epoxidcs l 175 o OCHO(.H CH CH= (EH11 176 oHOCH CH:CH

Table II Morphogenetic Effects of Representative Compounds in theTenebrio Gcnitalia Assay Compound Mierograms of Compound Required toNumber Produce the Indicated Morphogenetie Effects in Pupal-Adult Tablel Intermediates Pupal Genitalia Pupal adult intermediates represent anintermediate in which the insect molts to a monster with an essentiallypupal abdomen and an adultoid head and thorax. "Papal genitalia refersto the effect in which the insect is nearly adult but retains immaturegenitalia.

Each of the above morphogentic effects causes the insect to die shortlythereafter.

Table III Reduction in Adult Emergence and Egg Hatch of Mexican BeanBeetle Epilachna varivcstis Topical treatment of Z-da old prcpupac withan acetone solution of compound.

'-I'opical treatment by dipping egg masses in an acetone solution ofcompound. "An acetone control conducted for each of the above treatmentsshowed that the solvent contributed nothing to the effect of thecompounds.

. Table IV Morphogentic Effects of Representative Compounds on Tencbriopupae by Fumigation.

Compounds were spread over the lid of a 100 rrn diameter petri dish in asmall volume of acetone and after evaporation of the acetone the lid wasplaced over the bottom of the petri dish containing newly moltedTenebrio pupae. The pupuc were therefore exposed only to the vapors anddid not come in contact with the compound directly. The insects wereleft in the dish until they underwent the finnl molt toward the adult.

1 claim: 1. A method of controlling the maturation of insects selectedfrom the group consisting of Tenebrio molitor' (L.) and Epildchnavarivestis comprising applying to said insects at an immature stage ofgrowth-an effective maturation inhibiting amount of a compound of theformula where in Rand R are straight chain alkyls containing from one totwo carbon atoms; x is a number from 1 to 2; and Z is selected from thegroup consisting of in which n is a number from O to 3;

in which n'is a number from O to l; and

3 -HO(CH- ,),,CH

in which n is a number from 0 to 2.

2. The method of claim. 1 iniwhich Z is (CH;. O(CH CH and -n is a numberfrom O to 3.

3. Themethod of claim 2 in which R and R are methyl, x is 1, and n. isl. 5 4. The 'method of claim 2 in which R is ethyl, R is methyl, x is l,and ms 1. A

5. The method of claim 2 in which R and R are ethyl,

xis1,andnisl.

6. The method of claim 2 in which R and R are methyl, x is 1, and n is3. 7. The method of claim 1 in which Z is methyl, and x is l.

9. The method of claim 7 in which R and R are ethyl,

and x is 1.

10. The method of claim 1 in-which Z is CH2 )n 3 and n is a number from0 to 1. g 11. The method of claim 10 in which R and R are methyl, x is1, and n is O.

12. The-method of claim 1 in'which Z is 13. The method of claim 12 inwhich and R are methyl, and x is l.

14. The method of claim 1 in which Z is CH3 l and n is a number of O to2.

15. The method'of claim 14 in which R and R are methyl, x is l, and n is1.

16. The method of claim 1 in which the juvenile hormone mimickingcompound is applied topically.

17. The method of claim 1 in which the juvenile hormone mimickingcompound is applied as a fumigant.

18. The method of claim 1 in which the juvenile hormone mimickingcompound is applied as a solute in an inert organic solvent.

1. A METHOD OF CONTROLLING THE MATURATION OF INSECTS SELECTED FROM THEGROUP CONSISTING OF TENEBRO MOLITOR (L) AND EPILACHNA VARIVESTISCOMPRISING APPLYING TO SAID INSECTS AT AN IMMATURE STAGE OF GROWTH ANEFFECTIVE MATURATION INHIBITING AMOUNT OF A COMPOUND OF THE FORMULA 2.The method of claim 1 in which Z is -(CH2)2-O(CH2)n CH3 and n is anumber from 0 to
 3. 3. The method of claim 2 in which R and R'' aremethyl, x is 1, and n is
 1. 4. The method of claim 2 in which R isethyl, R'' is methyl, x is 1, and n is
 1. 5. The method of claim 2 inwhich R and R'' are ethyl, x is 1, and n is
 1. 6. The method of claim 2in which R and R'' are methyl, x is 1, and n is
 3. 7. The method ofclaim 1 in which Z is
 8. The method of claim 7 in which R and R'' aremethyl, and x is
 9. The method of claim 7 in which R and R'' are ethyl,and x is
 10. The method of claim 1 in which Z is
 11. The method of claim10 in which R and R'' are methyl, x is 1, and n is
 0. 12. The method ofclaim 1 in which Z is
 13. The method of claim 12 in which R and R'' aremethyl, and x is
 1. 14. The method of claim 1 in which Z is
 15. Themethod of claim 14 in which R and R'' are methyl, x is 1, and n is 1.16. The method of claim 1 in which the juvenile hormone mimickingcompound is applied topically.
 17. The method of claim 1 in which thejuvenile hormone mimicking compound is applied as a fumigant.
 18. Themethod of claim 1 in which the juvenile hormone mimicking compound isapplied as a solute in an inert organic solvent.